Reslizumab for Poorly Controlled, Eosinophilic Asthma: A
Randomized, Placebo-Controlled Study
Mario Castro,1 Sameer Mathur,2 Frederick Hargreave*,3 Louis-Philippe Boulet,4 Fang
Xie,5 James Young,6 H. Jeffrey Wilkins,5 Timothy Henkel,5 and Parameswaran Nair3 for
the Res-5-0010 Study Group
1Washington University School of Medicine, St. Louis, MO, United States; 2University
of Wisconsin, Madison, WI, United States; 3McMaster University, Hamilton, ON,
Canada; 4Institut Universitaire de cardiologie et de pneumologie de Québec, Québec, QC,
Canada; 5Cephalon, Inc., Frazer, PA, United States; 6United BioSource Corporation, Ann
Arbor, MI, United States
Corresponding Author: Mario Castro, Washington University School of Medicine, 660 S.
Euclid Ave, Campus Box 8052, St. Louis, MO 63110, email@example.com, phone: 314-
362-6904, fax; 314-362-2307.
This study was sponsored by Ception Therapeutics, Inc., which has since been acquired
by Cephalon, Inc.
ClinicalTrials.gov identification number: NCT00587288
Running title: Reslizumab in eosinophilic asthma
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AJRCCM Articles in Press. Published on August 18, 2011 as doi:10.1164/rccm.201103-0396OC
Copyright (C) 2011 by the American Thoracic Society.
MC, SM, FH, JY, HJW, TH, and PN designed the study and interpreted the data. MC,
SM, FH, LPB, and PN collected the data. FX and JY conducted the data analysis. MC
wrote the report with the support of a medical writer and coordinated author review. The
medical writer worked at the direction of MC and did not contribute to the study design
or data interpretation. All authors reviewed the manuscript and provided comment. MC
had full access to the study data and had final responsibility for the decision to submit the
manuscript for publication.
This article has an online data supplement, which is accessible from this issue’s table of
contents online at www.atsjournals.org
Page 2 of 45
Background: Eosinophilic asthma is a phenotype of asthma characterized by the
persistence of eosinophils in the airways. Interleukin-5 is involved in the activation and
survival of eosinophils. We evaluated the effect of the antibody to IL-5, reslizumab, in
patients with eosinophilic asthma that is poorly controlled with high-dose inhaled
Methods: Patients were randomly assigned to receive infusions of reslizumab 3.0 mg/kg
(n=53) or placebo (n=53) at baseline and weeks 4, 8, and 12, with stratification by
baseline Asthma Control Questionnaire (ACQ) score ≤2 or >2. The primary efficacy
measure was the difference between the reslizumab and placebo groups in the change in
ACQ score from baseline to end of therapy (week 15 or early withdrawal).
Findings: Mean changes from baseline to end of therapy in ACQ score were -0.7 in the
reslizumab group and -0.3 in the placebo group (p=0.054) and in forced expiratory
volume in 1 second (FEV1) were 0.18 and -0.08 L, respectively (p=0.002). In those
patients with nasal polyps, the changes in ACQ score were -1.0 and -0.1, respectively
(p=0.012). Median percentage reductions from baseline in sputum eosinophils were
95.4% and 38.7%, respectively (p=0.007). Eight percent of patients in the reslizumab
group and 19% of patients in the placebo group had an asthma exacerbation (p=0.083).
The most common adverse events with reslizumab were nasopharyngitis, fatigue, and
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Interpretation: Patients receiving reslizumab showed significantly greater reductions in
sputum eosinophils, improvements in airway function, and a trend toward greater asthma
control than those receiving placebo. Reslizumab was generally well tolerated.
Abstract word count: 254
Abstract limit: 300 words
Key words: eosinophils, asthma, interleukin-5, reslizumab
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Asthma is a chronic disease of the airways of the lungs characterized by airflow
obstruction and airway hyper-responsiveness and inflammation. While most patients
with asthma are able to control their symptoms with bronchodilators and low to moderate
doses of inhaled corticosteroids, some remain uncontrolled on high doses which can
result in time off from work or hospitalization (1, 2).
Eosinophilic asthma is a phenotype of asthma that is characterized by the persistence of
eosinophils in the lung and sputum. The numbers of eosinophils in the blood and
bronchial fluid can correlate with asthma severity(3). Eosinophils are involved in lung
tissue remodeling, including airway thickening and fibrosis, and angiogenesis, which
promotes further tissue growth and remodeling (4). Treatment strategies that aim to
reduce the level of eosinophils in the sputum have resulted in improved control of asthma
symptoms and fewer exacerbations (5, 6).
The proinflammatory cytokine interleukin-5 (IL-5) is a key mediator in the maturation,
recruitment, and activation of eosinophils (7). Inhibition of IL-5 has been shown to
reduce blood and sputum eosinophils in patients with asthma (8, 9). However, anti-IL-5
therapy was not effective at reducing the signs and symptoms of asthma in studies of
patients who were not selected according to their asthma phenotype (8-10). In contrast,
inhibition of IL-5 was effective as a prednisone-sparing therapy in patients with severe
prednisone-dependent asthma and increased eosinophils in their sputum (11).
Reslizumab is an IgG4/κ humanized monoclonal antibody comprised of the
complementarity determining regions of a murine antibody to human interleukin-5 that
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has been grafted onto human frameworks (12). Reslizumab neutralizes circulating IL-5
by preventing it from binding to eosinophils. The objective of this study was to evaluate
the effect of reslizumab on patients with eosinophilic asthma that was poorly controlled
with inhaled corticosteroids. Some of the results herein had previously been presented at
scientific meetings (13, 14).
Patients aged 18 to 75 years with asthma: 1) confirmed by airway hyperreactivity (a 20%
reduction in forced expiratory volume in 1 second [FEV1] after up to 16 mg/mL of
methacholine) or by airway reversibility (a ≥12% improvement in FEV1 after a beta
agonists); 2) treated with high-dose inhaled corticosteroids (≥440 µg of fluticasone twice
per day) in combination with at least one other agent (including short- or long-acting beta
agonists, leukotriene antagonists, and cromolyn sodium); 3) poorly controlled as
indicated by an Asthma Control Questionnaire (ACQ) (15) score of 1.5 or more; and 4)
associated with induced sputum eosinophils of 3% or more were eligible for the study.
Patients were excluded from the study if they were using systemic corticosteroids
(including oral corticosteroids), had a clinically significant comorbidity, or had
hypereosinophilic syndrome. Detailed methods are available in the Supplemental
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This randomized, double-blind, placebo-controlled study was conducted at 25 sites in the
United States and Canada between February 2008 and January 2010. Eligible patients
were randomly assigned to infusions of reslizumab 3.0 mg/kg or placebo (0.9% saline) in
a 1:1 ratio at baseline and weeks 4, 8, and 12. Reslizumab was infused at a rate no faster
than 2 mL per minute. All doses were administered in the same total volume for patients
of the same weight in order to maintain the study blind. Patients continued the doses of
inhaled corticosteroids that they were receiving at the beginning of the study.
Study site visits occurred at screening and weeks 4, 8, 12, and 15. End of therapy
assessments were conducted at week 15 (i.e., 3 weeks after the last dose of study
medication) or early withdrawal. For the purposes of randomization, patients were
stratified by baseline ACQ score (≤2 or >2). Each site’s institutional review board
approved the protocol. All patients provided written informed consent before
participating in the study.
The primary study endpoint was the difference between the reslizumab and placebo
groups in the change from baseline to end of therapy (week 15 or early withdrawal) in the
ACQ score (7-question instrument) (15). Other efficacy measures included spirometry,
blood and induced sputum eosinophil counts, and the percentage of patients with clinical
asthma exacerbations. A clinical asthma exacerbation was defined as 1) a 20% or more
decrease from baseline in FEV1, or 2) worsening of asthma requiring emergency
treatment, hospital admission, or 3 or more days of oral corticosteroid treatment. Patients
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with exacerbations were treated according to the investigator’s discretion. The presence
of nasal polyps was determined (at baseline only) through medical history, computed
tomography (at selected sites), and/or physical examination.
Assuming a difference of 0.5 between the reslizumab and placebo groups in the change in
ACQ score from baseline to end of therapy, a standard deviation of 0.76, and a
significance level of 0.05, we expected that a sample size of 120 patients (60 per
treatment group) would provide over 90% power to detect a difference between the
Changes from baseline to end of therapy in continuous variables (ACQ score, FEV1,
percentage of the predicted value for FEV1, and sputum eosinophils) were analyzed using
an analysis of covariance, adjusting for the stratification factor (ACQ ≤2 or ACQ >2) and
the baseline values for the variable being analyzed. Least square means were used to
determine the mean differences between reslizumab and placebo. Changes from baseline
to multiple time points in ACQ score and FEV1 were analyzed using a mixed-effects
model, repeated-measures analysis of covariance, adjusting for the stratification factor
and the baseline values for the variable being analyzed. For the primary efficacy
analysis, if a patient had a missing ACQ score at the end of therapy visit, the last
observation was carried forward and used as the end of therapy value. The incidence of
clinical asthma exacerbations was analyzed using logistic regression, adjusting for the
stratification factor. A subgroup analysis of patients with nasal polyps was prespecified.
Subgroup analyses of disease duration and baseline sputum and blood eosinophil levels
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were performed post hoc. All analyses were tested using 2-sided hypotheses at the α =
0.05 level and were conducted using SAS version 9.1.
Role of Funding Source
The study was sponsored by Ception Therapeutics, Inc. which has since been acquired by
Cephalon, Inc. Ception employees were involved in the study design and data
interpretation. Data analysis was conducted by United BioSource, Inc. employees, with
funding from Ception, and Cephalon employees. Former Ception employees and current
Cephalon and United BioSource employees contributed to the preparation of the
manuscript and are listed as authors, as appropriate. SM, FH, LP and PN had unrestricted
opportunity to examine and interpret the data and prepare the manuscript. MC had full
access to the study data and had final responsibility for the decision to submit the
manuscript for publication.
A total of 479 patients were screened, and 106 patients were randomized (Figure 1).
Three patients in the reslizumab group and 9 in the placebo group withdrew from
treatment; 10 of the 12 withdrawals were attributable to a lack of efficacy. The mean age
was 45.4 years, the mean time since asthma diagnosis was 24.7 years, and the mean
baseline ACQ score was 2.7 (range: 1.6 to 5.1). The median percentage of eosinophils in
the induced sputum sample was 10.0% and was significantly greater in those patients
with nasal polyps. The treatment groups were generally well balanced with regard to
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baseline demographics (Table 1). Imbalances in disease characteristics were the result of
chance since all patients were randomly assigned to treatment groups.
We compared the efficacy of reslizumab with placebo for the primary outcome measure
of asthma control (Table 2, Figure 2A). The mean change from baseline to end of
therapy in ACQ score was -0.7 in the reslizumab group and -0.3 in the placebo group
(p=0.0541). Significant improvements in ACQ scores were observed in the reslizumab
group versus placebo in the stratum of patients with baseline ACQ scores >2 (p=0.0505)
and in those with nasal polyps (p=0.0119) (Table 3). Overall, 59% of patients in the
reslizumab group and 40% of patients in the placebo group achieved an improvement of
≥0.5 in the ACQ score (odds ratio [95% confidence interval] 2.06 [0.88 to 4.86], p =
0.0973), which is considered to be the minimal clinically significant change (16).
We then examined the effect of reslizumab in comparison with placebo on airway
function (Table 2). Patients in the reslizumab group showed statistically significant
improvements from baseline in FEV1 (p=0.0023), percentage of the predicted FEV1
(p=0.0010), and forced vital capacity (FVC) (p=0.0054) than those in the placebo group
(Table 2, Figure 2B).
We then evaluated the effect of reslizumab in comparison with placebo on sputum and
blood eosinophils. Patients in the reslizumab group showed significantly greater
reductions from baseline in eosinophils in the induced sputum (Table 2, Figure 3A) and
in blood eosinophil counts (Table 2, Figure 3B) than those in the placebo group.
Reductions in the reslizumab group were observed as early as the first assessment at
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week 4. By the end of therapy, the median percentage reduction in the percentage of
eosinophils in the induced sputum was 95.4% in the reslizumab group and 38.7% in the
placebo group (p=0.0068) (Table 2). Actual sputum and blood eosinophil data at each
visit are shown in the Supplemental Material.
One patient in the reslizumab group and 1 patient in the placebo group had sputum
eosinophil values at end of therapy that were outliers in the data set. The patient in the
placebo group had a clinical asthma exacerbation during the study, but the patient in the
reslizumab group did not have an exacerbation. Sputum and blood eosinophil levels at
baseline and end of therapy for these patients are provided in the Supplemental Material.
Among asthma patients with nasal polyps, we observed a statistically significantly greater
improvement from baseline to end of therapy in ACQ score in the reslizumab group
compared with the placebo group (Table 3), while no such decrease was observed among
patients without nasal polyps. Differences between the treatment groups were observed
in the changes from baseline to end of therapy in FEV1 values for both patients with nasal
polyps and patients without nasal polyps. Results of post hoc analyses of subgroups of
disease duration and baseline sputum or blood eosinophils are also shown in Table 3.
Exacerbations occurred in four patients (8%) in the reslizumab group and 10 (19%) in the
placebo group (odds ratio [95% confidence interval]: 0.33 [0.10, 1.15], p=0.0833). Two
of the four exacerbations in the reslizumab group occurred before the second dose of
study medication. Of the patients in the reslizumab group with exacerbations, one had a
20% decrease from baseline in FEV1, 3 required emergency treatment for asthma, one
was admitted to the hospital for asthma, and all 4 required ≥3 days of oral corticosteroid
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treatment for asthma worsening. Of the patients in the placebo group with exacerbations,
5 had a 20% decrease from baseline in FEV1, 4 required emergency treatment for asthma,
and 4 required ≥3 days of oral corticosteroid treatment for asthma worsening. Additional
information about the patients with exacerbations, including sputum and blood eosinophil
data, is provided in the Supplemental Material.
The proportions of patients in the treatment groups with adverse events were similar
(Table 4). Adverse events were generally mild or moderate in severity. The most
common adverse event was nasopharyngitis, which occurred in 11 patients (21%) in the
reslizumab group and 5 patients (9%) in the placebo group. Of the patients with
nasopharyngitis adverse events, 8 patients in the reslizumab group and 2 patients in the
placebo group also had nasal polyps at baseline. No clinically meaningful changes in
laboratory values or vital signs were observed.
Serious adverse events occurred in two patients in the reslizumab group (pneumonia and
worsening of asthma) and one patient in the placebo group (hypertension). The patient
with worsening of asthma was the only patient in the reslizumab group who discontinued
study treatment because of an adverse event. One patient in the placebo group also
discontinued study treatment because of an adverse event (generalized pruritis).
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In this multi-center study, we identified patients with an eosinophilic asthma phenotype a
priori that was uncontrolled with high-dose inhaled corticosteroids and at least one other
agent and then provided targeted therapy with a monoclonal antibody to IL-5, reslizumab.
The results show that patients with this phenotype who received reslizumab had a
significantly greater improvement in airway function and reduction in sputum and blood
eosinophil counts than those who received placebo. Modest improvement in asthma
control was also observed with reslizumab, but the difference between the treatment
groups did not reach statistical significance. However, the improvements in asthma
control were greater in patients with nasal polyposis, a hallmark of eosinophilic disease in
patients with asthma (17, 18). These results provide evidence that inhibition of IL-5 in
patients with the eosinophilic asthma on high dose inhaled corticosteroids reduces airway
eosinophilia and that such a reduction improves clinical outcomes in these patients.
Early studies of anti-IL-5 therapy in patients with severe asthma did not include
consideration of the pathophysiological asthma phenotype to determine which patients
should be selected for such therapy (8-10). The reduction of eosinophils in the blood and
sputum of patients who received anti-IL-5 therapy in these studies was not associated
with improvement in airway function. In our study, sputum eosinophilia was a
requirement for study entry, and patients who received reslizumab showed statistically
significant improvements in airway function and a trend towards improved asthma
control versus placebo.
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Two recent studies demonstrated that when patients were selected with eosinophilic
asthma there was clinical improvement. In one of these, 61 patients with refractory
eosinophilic asthma, Haldar et al (19) demonstrated that inhibition of IL-5 reduced
asthma exacerbations over one year though there was no significant effect on FEV1. In
this study, demonstration of eosinophilia was only required at some point in the previous
two years. In contrast, our study required persistent airway eosinophilia at
randomization. Establishing a persistent eosinophilic phenotype appears critical in
determining the optimal response to anti-IL-5 therapy (20). In the other study of 9
patients with severe prednisone-dependent asthma with persistent airway eosinophilia,
Nair et al (11) demonstrated that treatment with anti-IL-5 reduced asthma exacerbations
and the need for prednisone while improving asthma control and FEV1. In our 15-week
study, few patients in either treatment group experienced exacerbations even though their
baseline asthma control was worse than that observed in the Haldar et al study (19).
Although the percentage of exacerbations in the reslizumab group was lower than that in
the placebo group, the difference between the treatment groups did not reach statistical
significance, probably because of the short duration of the study.
A novel aspect of the current study was the effect of reslizumab in those patients with
uncontrolled asthma and nasal polyposis (Table 3). Nasal polyposis with or without
chronic rhinosinusitis is due to chronic airway inflammation with abundant eosinophils
and interferon-γ, IL-4, IL-5 and IL-13 production (21-23). Furthermore, the mechanism
of tissue eosinophilia in nasal polyposis is due to the delay of eosinophil apoptosis
induced by IL-5 (24). A previous study of reslizumab in patients with chronic
rhinosinusitis and nasal polyposis demonstrated that the best predictor of nasal symptom
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response to this therapy was nasal IL-5 levels (25). Therefore, it is likely that this subset
of patients with nasal polyposis have a disease process that is driven in part by
eosinophils, as demonstrated by their higher baseline blood and sputum eosinophil levels,
and responsive to inhibition of IL-5.
Reslizumab was generally well tolerated. The overall incidence of adverse events in the
reslizumab group was similar to that of the placebo group, and most adverse events were
mild or moderate in severity. Only nasopharyngitis occurred more frequently in the
reslizumab group than the placebo group, and this may have been the result of the
disparity between the treatment groups in nasal polyps, since most of the patients with
nasopharyngitis adverse events had nasal polyps at baseline. When upper respiratory
adverse events were combined, the incidence in the reslizumab group was similar to that
in the placebo group.
Previous studies have demonstrated a link between persistent airway eosinophilia and the
subsequent exacerbations of asthma (26). Furthermore, management strategies aimed at
reducing sputum eosinophilia have demonstrated a reduction in exacerbations without an
increase in need for corticosteroid use (5, 6). Together with the studies of mepolizumab
(11, 19), these results suggest that reducing airway eosinophilia with anti-IL-5 therapy
should reduce exacerbations of asthma. In our study, we observed a trend in this
direction; however, the 15-week duration of this study limits the interpretive value of the
results. The study may not have been long enough to evaluate the effect of reslizumab on
clinical asthma exacerbations since few exacerbations were observed even in the placebo
group. In addition, our study did not enroll subjects who were taking oral corticosteroids
or who had previous exacerbations requiring systemic corticosteroids. Therefore, the low
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